Imidazo[2,1-b]thiazole and thiazolo[3,2-a]-benzimidazole quaternary salts as hypoglycemic agents and growth promotants

ABSTRACT

7-Substituted imidazo[2,1-b]thiazolium and 9-substituted thiazolo-[3,2-a]benzimidazolium salts as blood-sugar lowering agents and growth promotants.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 507,384 filedSept. 19, 1974 and now U.S. Pat. No. 3,954,784.

BACKGROUND OF THE INVENTION

This invention relates to compounds having hypoglycemic and/or growthpromotant properties, said compounds being quaternary 7-substitutedimidazo [2,1-b]-thiazolium and 9-substitutedthiazolo[3,2-a]benzimidazolium salts.

Other than insulin, which is usually administered subcutaneously, themost useful oral medication employed in the treatment of diabetes arethe sulfonylureas, many of which are currently being marketed. Inaddition, biguanides are also employed either alone or in combinationwith sulfonylureas in the treatment of this disease.

More recently, 1-substituted 3-(2-pyrimidinyl)imidazolium salts havebeen claimed in Belgium Pat. No. 743,510 and German Pat. Application No.1,964,282, to be active as hypoglycemic agents. Japanese PatentApplication 7305899 reports the synthesis of pyridimium-pyrazine andtheir use as lowerers of blood sugar and free fatty acid levels.Weigand, et al., J. Med. Chem., 15, 1326 (1972), review and report onthe hypoglycemic activity of a number of azolylpyridinium salts.

Most commonly employed growth promotants are members of theantibacterial class of quinoxaline-di-N-oxides.

2,3,9-Trimethylbenzimidazo[2,1-b]thiazolium iodide has been prepared byde Stevens, et al., J. Am. Chem. Soc., 79, 5710 (1957), andimidazo[2,1-b]-thiazolium by Kondo, et al., J. Pharm. Soc., Japan, 57,1050 (1937) (C.A. 32, 3398 (1938) and Kickhofen, et al., Chem. Ber., 88,1109 (1955) (C.A. 50, 13911 (1956).

SUMMARY OF THE INVENTION

It has now been discovered that quaternary compounds of the formula##STR1## wherein X is a pharmaceutically acceptable anion; R₁ is alkylhaving from twelve to eighteen carbon atoms, propargyl, allyl, benzyl,phenethyl, styryl, phenylallyl or substituted benzyl wherein saidsubstituent is fluoro, chloro, methoxy, trifluoromethyl, methyl, cyano,phenyl or dichloro; R₂ is hydrogen or alkyl having from one to threecarbon atoms; R₃ is hydrogen, alkyl having from one to three carbonatoms, adamantyl, phenyl or substituted phenyl wherein said substituentis dimethyl or dimethoxy; R₂ and R₃ when taken together istetramethylene; R₄ is hydrogen, alkyl having one to three carbon atoms,phenyl, dimethylphenyl or chlorophenyl; R₅ is hydrogen; and R₄ and R₅when taken together with the carbon atoms to which they are attachedform a 1,2-phenylene ring.

The broken line shown in the above structure represents an optional bondsuch that the present invention is meant to embrace both the5,6-dihydro- and dehydro- forms of the imidazo[2,1-b]thiazoliumcompounds.

A preferred group of hypoglycemic compounds are those wherein R₁ isbenzyl, R₂, R₄ and R₅ are each hydrogen and R₃ is said alkyl oradamantyl.

A second preferred group are those wherein R₁ is chlorobenzyl, R₂, R₄and R₅ are each hydrogen and R₃ is alkyl containing from 1 to 3 carbonatoms.

A third preferred group included those compounds wherein R₂, R₃ and R₅are each hydrogen and R₄ is phenyl or dimethylphenyl.

A fourth preferred group of hypoglycemic compounds are those wherein R₁is benzyl or substituted benzyl, R₂ is hydrogen, R₃ is methyl and R₄ andR₅ taken together with the carbon atoms to which they are attached forma 1,2-phenylene ring.

A fifth preferred class of compounds of the present invention which aregrowth promotants are those wherein R₁ is alkyl having twelve toeighteen carbon atoms, R₂, R₄ and R₅ are each hydrogen and R₃ is alkylhaving one to three carbon atoms.

In all the aforementioned preferred groups of growth promotants andblood sugar lowering agents, it is preferred that X is chloro or bromo.

DETAILED DESCRIPTION OF THE INVENTION

The hypoglydemic agents of the present invention are synthesized byreactions depicted in the following scheme: ##STR2## wherein X and Z arechloro or bromo and R₁, R₂, R₃, R₄ and R₅ are as previously indicated.

Experimentally, equimolar amounts of the appropriate 2-mercaptoimidazoleor 2-mercapto-4,5-dihydroimidazole and requisite α-halocarbonyl reagentare contacted in a reaction-inert solvent to yield the intermediatecompounds 1 as the hydrogen halide salt.

Reaction times and temperatures are not critical. In general, it ispreferred that steam bath temperatures be employed in order to hastenthe completion of said reaction. Under these conditions the reaction isusually complete in 1-4 hours.

Although the preparation of compounds 1 can be conducted without asolvent, i.e. neat, it is preferred that a solvent be employed. Further,it is preferred that such a solvent be a reaction-inert solvent, i.e.one which will not react with the product or starting reagents to anyappreciable extent. Such a solvent should be a non-aqueous, polarsolvent and include, for example, lower alkanols, lower alkylnitriles,or dialkyl ketones. The preferred solvent is ethanol.

The reaction product can be isolated from the completed reaction byremoval of the solvent or, alternately, by cooling the reaction mixtureto induce crystallization of the hydrogen halide salt. When theintermediates 1 have been isolated as the salt they are then convertedto the free base by treating an aqueous solution or suspension of saidsalt with sufficient aqueous sodium hydroxide to liberate the free base,which can be filtered or extracted with a water immiscible solvent.

An alternate method for the preparation of intermediate imidazo[2,1-b]thiazoles is as follows: ##STR3## wherein R₂, R₃, R₄, R₅ and Z are aspreviously indicated.

The condensation reaction outlined above is conducted in the same manneras that wherein the starting reagents are a mercaptoimidazole derivativeand a halo carbonyl compound. Further, isolation of the product andgeneration of the free base is effected in the same manner.

Transformation of compounds of formula 1 to quaternary salts of formula2 is effected by reacting 1 with a halide, R₁ X, where X is chloro,bromo or iodo. Said reaction can be conducted between equimolar amountsof the two reagents either neat or in the presence of a suitablereaction-inert solvent. When conducted neat a large excess of the halidecan be employed, acting under these conditions as both a reactant andsolvent.

As previously indicated, by a reaction-inert solvent is meant one whichdoes not react to any appreciable degree with the product or reactantsunder the conditions of said reaction. Solvents suitable for thesolubilizing of the reactants leading to the quaternary compounds 2 canbe of a varied nature, and can include (lower)alkanols,(lower)alkylnitriles, di(lower)alkyl ketones, cyclic- and di(lower)alkylethers and liquid aromatic hydrocarbons. The preferred solvent for thisreaction is acetonitrile.

Reaction time is not critical, and depends on temperature, concentrationand inherent reactivity of the reagents. When steam bath temperaturesare employed, completion of the reaction usually requires 2 to 4 hours.

The product is isolated by cooling the reaction mixture to inducecrystallization, or initial concentration of the reaction mixturefollowed by cooling. Further purification of the final product isfacilitated by trituration or recrystallization from an appropriatesolvent.

As mentioned previously, quaternary salt formation is preferablyeffected with RX wherein X is bromo, chloro or iodo. Following isolationof these salts the nature of the X variable can be altered by initiallytreating an aqueous solution of quaternary halide with an equivalent ofsilver oxide, followed by separation of the precipitated silver halideand treatment of the aqueous solution of the quaternary base with atleast an equivalent of an appropriate acid HX.

Alternately, the quaternary base can be obtained by passing a solutionof a salt through a basic ion-exchange resin column followed bytreatment of the eluate with the same or a different acid.

In the utilization of the chemotherapeutic activity of these compoundsof the present invention which form quaternary salts, it is preferred,of course, to use pharmaceutically acceptable salts. Althoughwater-insolubility, toxicity, or lack of crystalline nature may makesome particular salt species unsuitable or less desirable for use assuch in a given pharmaceutical application, the water insoluble or toxicsalts can be converted to the corresponding pharmaceutically acceptablequaternary hydroxide by decomposition of the salt as described above, oralternately they can be converted to any desired pharmaceuticallyacceptable quaternary salt.

Examples of pharmaceutically acceptable anions other than the halidesare nitrate, sulfate, phosphate, alkanoates, lactate, citrate, tartrate,succinate and maleate.

Imidazo[2,1-b]thiazole intermediates are prepared by the aforementionedprocedures, said procedures being familiar to those skilled in the artand employed in the synthesis of such compounds as reported by Wilson,et al., J. Chem. Soc., 1955, 2943, Fefer, et al., J. Org. Chem, 26, 828(1961), U.S. Pat. Nos. 2,969,369; 3,267,112 and 3,274,209, Iwai, et al.,Chem. Pharm. Bull. (Tokyo), 12, 813 (1964), Todd, et al., Chem. Ber.,69, 217 (1936), Kondo, et al, J. Pharm. Soc. Japan, 57, 1050 (1937) andKickhofen, et al., Chem. Ber., 88, 1109 (1955).

The more fundamental starting materials employed in the preparation ofthe imidazo[2,1-b]thiazoles, i.e., the mercaptoimidazole derivatives,α-halo carbonyl reagents and the 2-aminothiazoles are available eithercommercially or by synthetic procedures familiar to those skilled in theart.

The imidazo[2,1-b]thiazole and thiazolo[3,2-a]benzimidazole quaternarysalts adapted to the therapeutic use as oral hypoglycemic agents arethose wherein R₁ is propargyl, benzyl, phenethyl or said substitutedbenzyl and R₂, R₃, R₄ and R₅ are as previously defined. Preferred withinthis group are 3-methyl-7-benzyl-5,6-dihydroimidazo[2,1-b]thiazoliumchloride, 3-methyl-7-benzylimidazo[ 2,1-b]thiazolium chloride,3-methyl-7-(o-chlorobenzyl)imidazo[2,1-b]thiazolium chloride,3-methyl-7-(p-chlorobenzyl)imidazo[2,1-b]thiazolium chloride,6-phenyl-7-benzylimidazo[2,1-b]thiazolium chloride,3-methyl-9-benzylthiazolo [3,2-a]benzimidazolium bromide,3-adamantyl-7-benzyl-5,6-dihydroimidazo[2,1-b]- thiazolium bromide,6-(2,4-dimethylphenyl)-7-benzylimidazo[2,1-b]thiazolium bromide,3-methyl-9-(m-trifluoromethylbenzyl)thiazolo[3,2-a]benzimidazoliumbromide. Those compounds of the present invention which are useful asanimal growth promotants are those wherein R₁ is alkyl having twelve toeighteen carbon atoms, allyl, styryl or phenylallyl and R₂, R₃, R₄ andR₅ are as previously defined. Preferred within this group is3-methyl-7-cetyl-5,6-dihydroimidazo[ 2,1-b]thiazolium bromide.

The imidazo[2,1-b]thiazolium and thiazolo[3,2-a]benzimidazoliumquaternary salts, which are useful hypoglycemic agents in mammals, canbe administered either as individual therapeutic agents or as mixturesof therepeutic agents. They can be administered alone, but are generallyadministered with a pharmaceutical carrier selected on the basis of thechosen route of administration and standard pharmaceutical practice. Forexample, they may be combined with various pharmaceutically acceptablecarriers in the form of tablets, capsules, lozenges, troches, hardcandies, powders, aqueous suspensions or solutions, injectablesolutions, elixirs, syrups and the like. Such carriers include soliddiluents or filters, sterile aqueous media and various nontoxic organicsolvents. Moreover, the oral pharmaceutical compositions of thisinvention may be suitably sweetened and flavored by means of variousagents of the type commonly used for this purpose.

The particular carrier selected and the proportion of active ingredientto carrier are influenced by the solubility and chemical nature of thetherapeutic compounds, the chosen route of administration and the needsof the standard pharmaceutical practice. For example, where thosecompounds are administered orally in tablet form, excipients such aslactose, sodium citrate, calcium carbonate and dicalcium phosphate maybe used. Various disintegrants such as starch, alginic acids, andcertain complex silicates, together with lubricating agents such asmagnesium stearate, sodium lauryl sulphate and talc, may also be used inproducing tablets for the oral administration of these compounds. Fororal administration in capsule form, high molecular weight polyethyleneglycols are among the preferred materials for use as pharmaceuticallyacceptable carriers. Where aqueous suspensions are to be used for oraladministration, the compounds of this invention may be combined withemulsifying or suspending agents. Diluents such as ethanol, propyleneglycol, glycerine and their combinations may be employed as well asother materials.

For purposes of parenteral administration, solutions or suspensions ofthe instant compounds in sesame or peanut oil or in aqueous propyleneglycol solutions can be employed, as well as sterile aqueous solutionsdescribed hereinafter. These particular solutions are especially suitedfor intramuscular and subcutaneous injection purposes. The aqueoussolutions dissolved in pure distilled water are also useful forintravenous injection purposes provided that their pH is properlyadjusted beforehand. Such solutions should also be suitably buffered, ifnecessary, and the liquid diluent first rendered isotonic withsufficient saline.

It is necessary that the active ingredient form a proportion of thecomposition such that a suitable dosage form will be obtained.Obviously, several dosage unit forms may be administered at about thesame time. Although compositions with less than 0.005 percent by weightof active ingredient might be used in certain instances, it is preferredto use compositions containing not less than 0.005 percent of the activeingredient; otherwise the amount of carrier becomes excessively large.Activity increases with the concentration of the active ingredient. Thecomposition may contain 10, 50, 75, 95, or an even higher percentage byweight of the active ingredient.

Although the use of the present invention is directed toward thetreatment of mammals in general, the preferred subject is humans. Indetermining an efficacious dose for human therapy, results of animaltesting are frequently extrapolated and a correlation is assumed betweenanimal test behavior and proposed human dosage. When a commerciallyemployed standard is available, the dose level of the clinical candidatein humans is frequently determined by comparison of its performance withthe standard in an animal test. For example, β-phenethylbiguanide isemployed as a standard hypoglycemic agent and is administered to humansat the rate of 50 to 150 mg. daily. It is assumed, then, that ifcompounds of the present invention have activity comparable toβ-phenethylbiguanide in the test assay, that similar doses will providecomparable responses in humans.

Obviously, the physician will ultimately determine the dosage which willbe most suitable for a particular individual, and it will vary with theage, weight and response of the particular patient as well as with thenature and extent of the symptoms and the pharmacodynamiccharacteristics of the particular agent to be administered. Generally,small doses will be administered initially, with a gradual increase inthe dosage until the optimum level is determined. It will often be foundthat when the composition is administered orally, larger quantities ofthe active ingredient will be required to produce the same level asproduced by a small quantity administered parenterally.

Having full regard for the foregoing factors, it is considered that aneffective daily dosage of the compounds of the present invention inhumans of approximately 50 to 600 mg. per day, with a preferred range ofabout 50 to 400 mg. per day in single or divided doses, or at about 0.07to 0.6 mg./kg. of body weight will effectively lower blood sugar levelsin human diabetic subjects. These values are illustrative, and theremay, of course, be individual cases where higher or lower dose rangesare merited.

For use as a growth promotant or agent for improving feed conversionefficiency in animals, the compounds of the invention will generally beadministered in the animal feed or drink. For convenience ofdistribution, a compound will normally be marketed in the form of aconcentrate in which the compound is mixed with an inert diluent such aslimestone or oystershell powder or with other feed components. It isexpected that the compounds of the invention would be used at a level offrom 1 to 500 g. per ton of feed or 1 to 500 mg. per litre of drinkingwater, or at correspondingly higher levels in concentrates forsubsequent mixture with the feed or drinking water.

Thus the present invention yet further provides an animal food or drink,or a concentrate for addition thereto, containing one or more of thepreviously described compounds, and also a method of improving thegrowth, feed conversion efficiency of an animal which comprisesadministering to the animal an effective amount of one or more of thegrowth promotant compounds previously described.

The following examples are provided solely for the purpose ofillustration and are not to be construed as limitations of thisinvention, many variations of which are possible without departing fromthe spirit or scope thereof.

EXAMPLE 1 7-Propargyl-3-methyl-5,6-dihydroimidazo[2,1-b]thiazoliumbromide (R₁ = CH.tbd.CCH₂ ; R₂ = H; R₃ = CH₃ ; R₄ and R₅ = H; X = Br)

A solution of 12 g. of propargyl bromide and 14 g. of3-methyl-5,6-dihydroimidazo[2,1-b]thiazole (prepared by basification of3-methyl-5,6-dihydroimidazo [2,1-b]thiazole hydrochloride with 5N sodiumhydroxide solution) in 160 ml. of dry acetonitrile is allowed to stir atroom temperature for 16 hrs. The solution is concentrated to a smallvolume and the precipitated product filtered. The purified product isobtained by recrystallization from acetonitrile-ethyl acetate, 21 g.,m.p. 207°-208° C.

Anal. Calc'd for C₉ H₁₁ BrN₂ S: N, 10.8; Br: 30.9.Found: N, 10.5; Br:31.2.

EXAMPLE 2

Employing the procedure of Example 1, and starting with the requisitereagents, heating them under reflux for 16 hours, the following5,6-dihydrocongeners are synthesized: ##STR4##

    __________________________________________________________________________    R.sub.1   R.sub.2                                                                           R.sub.3   R.sub.4                                                                           R.sub.5                                                                           X  m.p.,° C.                           __________________________________________________________________________    C.sub.6 H.sub.5 CH.sub.2                                                                H   H         H   H   Br 147-149                                    C.sub.6 H.sub.5 CH.sub.2                                                                H   CH.sub.3  H   H   Br 138                                        C.sub.6 H.sub.5 CH.sub.2                                                                H   C.sub.6 H.sub.5                                                                         H   H   Br 185-186                                    C.sub.6 H.sub.5 CH.sub.2                                                                CH.sub.3                                                                          CH.sub.3  H   H   Br 140                                        C.sub.6 H.sub.5 CH.sub.2                                                                (CH.sub.2).sub.4                                                                             H  H   Br 177                                        2-ClC.sub.6 H.sub.4 CH.sub.2                                                            H   CH.sub.3  H   H   Br 221-223                                    3-ClC.sub.6 H.sub.4 CH.sub.2                                                            H   CH.sub.3  H   H   Br 177-180                                    4-ClC.sub.6 H.sub.4 CH.sub.2                                                            H   CH.sub.3  H   H   Cl 205-208                                    2,4-Cl.sub.2 C.sub. 6 H.sub.3 CH.sub.2                                                  H   CH.sub.3  H   H   Cl 272-275                                    2,6-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                   H   CH.sub.3  H   H   Br 243-245                                    3-FC.sub.6 H.sub.4 CH.sub.2                                                             H   CH.sub.3  H   H   Br 170-171                                    4-FC.sub.6 H.sub.4 CH.sub.2                                                             H   CH.sub.3  H   H   Br 218-219                                    3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                     H   CH.sub.3  H   H   Br 168-170                                    4-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                    H   CH.sub.3  H   H   Br 191-192                                    4-C.sub.6 H.sub.5 C.sub.6 H.sub.4 CH.sub.2                                              H   CH.sub.3  H   H   Br 186-187                                    C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                       H   CH.sub.3  H   H   Br 117-120                                              (CH.sub.2).sub.4                                                                            H   H   Br 196-198                                    C.sub.6 H.sub.5 CH.sub. 2                                                               H   2,5-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                  H   H   Br 161-163                                    C.sub.6 H.sub.5 CH.sub.2                                                                H   2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                    H   H   Br 203-205                                    C.sub.6 H.sub.5 CH.sub.2                                                                CH.sub.3                                                                          C.sub.6 H.sub.5                                                                         H   H   Br 210-213                                    C.sub.6 H.sub.5 CH.sub.2                                                                H                                                                                  ##STR5## H   H   Br 182-185                                    CH.sub.3 (CH.sub.2).sub.14 CH.sub.2                                                     H   CH.sub.3  H   H   Br 108-110                                    4-NCC.sub.6 H.sub.4 CH.sub.2                                                            H   CH.sub.3  H   H   Br 212                                        2-CH.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                     H   CH.sub.3  H   H   Br 201-204                                    C.sub.6 H.sub.5 CHCHCH.sub.2                                                            H   CH.sub.3  H   H   Cl 150-151                                    CH.sub.2CHCH.sub.2                                                                      H   CH.sub.3  H   H   Br 89-90                                      CH.sub.3 (CH.sub.2).sub.14 CH.sub.2                                                     H   C.sub.6 H.sub.5                                                                         H   H   Br 169- 170                               

The procedure of Example 1 is again repeated, starting with theappropriate 5,6-dihydroimidazo[2,1-b]thiazole and halide (R₁ X) toprovide the following compounds:

2-ethyl-3,6-dimethyl-7-(p-trifluoromethylbenzyl)-5,6-dihydroimidazo-[2,1-b]thiazoliumchloride,2-i-propyl-6-phenyl-7-(p-trifluoromethylbenzyl)-5,6-dihydroimidazo[2,1-b]thiazolium chloride,2-methyl-3-(2,4-dimethylphenyl)-7-(p-phenylbenzyl)-5,6-dihydroimidazo[2,1-b]thiazoliumbromide,3-(3,5-dimethylphenyl)-6-ethyl-7-(o-methoxybenzyl-5,6-dihydroimidazo[2,1-b]thiazoliumbromide,2,3-di-n-propyl-6-(m-chlorophenyl)-7-(p-chlorobenzyl)-5,6-dihydroimidazo[2,1-b]thiazoliumchloride, 3-adamantyl-6-phenyl-7-(o-fluorobenzyl)-5,6-dihydroimidazo[2,1-b]thiazolium chloride,3-(2,4-dimethylphenyl-6-(3,5-dimethylphenyl)-7-benzyl-5,6-dihydroimidazo[2,1-b]thiazoliumchloride,2-methyl-3-(3,5-dimethoxyphenyl)-6-(p-chlorophenyl)-7-(m-trifluoromethylbenzyl)-5,6-dihydroimidazo[2,1-b]thiazoliumbromide, 3-adamantyl-7-propargyl-5,6-dihydroimidazo[2,1-b]thiazoliumbromide,2,3,6-triethyl-7-(p-chlorobenzyl)-5,6-dihydroimidazo[2,1-b]-thiazoliumchloride,1-(m-trifluoromethylbenzyl)-2,3-dimethyl-2,3,5,6,7,8-hexahydroimidazo[2,1-b]benzthiazoliumchloride and1-benzyl-2-phenyl-2,3,5,6,7,8-hexahydroimidazo[2,1-b]benzthiazoliumbromide.

EXAMPLE 4 3-Methyl-7-benzylimidazo[2,1-b]thiazolium bromide (R₁ = C₆H.sub. 5 CH₂ ; R₂ = H; R₃ = CH₃ ; R₄ and R₅ = H; X = Br)

Nineteen grams of 3-methylimidazo[2,1-b]thiazole, obtained by treating23.2 g. of the hydrochloride salt in 300 ml. of water with sufficient20% sodium hydroxide solution to render it strongly basic, is dissolvedin 250 ml. of acetonitrile and subsequently treated with 27.4 g. ofbenzyl bromide. The reaction mixture is heated under reflux for 2 hrs.,and it is then cooled and treated with 150 ml. of diethyl ether. Theproduct is filtered and recrystallized from acetonitrile-ethyl acetate,37.4 g., m.p. 165°-167.5° C.

Anal. Calc'd for C₁₃ H₁₃ BrN₂ S: C, 50.5; H, 4.2; N, 9.1. Found: C,50.2; H, 4.3; N, 9.2.

EXAMPLE 5

Starting with the appropriate imidazo[2,1-b]thiazole and requisitehalide, and repeating the procedure of Example 4, the followingquaternary salts are prepared: ##STR6##

    __________________________________________________________________________    R.sub.1   R.sub.2                                                                          R.sub.3                                                                            R.sub.4 R.sub.5                                                                          X  m.p., ° C.                             __________________________________________________________________________    C.sub.6 H.sub.5 CH.sub.2                                                                H  H   CH.sub.3 H  Br 220                                           C.sub.6 H.sub.5 CH.sub.2                                                                H  H   C.sub.6 H.sub.5                                                                        H  Br 176-178                                       C.sub.6 H.sub.5 CH.sub.2                                                                H  H   p-ClC.sub.6 H.sub.4                                                                    H  Br 195-197                                       o-ClC.sub.6 H.sub.4 CH.sub.2                                                            H  CH.sub.3                                                                          H        H  Cl 174-177                                       m-ClC.sub.6 H.sub.4 CH.sub.2                                                            H  CH.sub.3                                                                          H        H  Cl 156-159                                       2,6-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                   H  CH.sub.3                                                                          H        H  Cl 225-229                                       2,4-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                   H  CH.sub.3                                                                          H        H  Cl 269-271                                       p-ClC.sub.6 H.sub.4 CH.sub.2                                                            H  CH.sub.3                                                                          H        H  Cl 206-209                                       p-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                    H  CH.sub.3                                                                          H        H  Cl 136-139                                       C.sub.6 H.sub.5 CH.sub.2                                                                H  CH.sub.3                                                                          H        H  Cl 152-155                                       C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                       H  CH.sub.3                                                                          H        H  Br 206-209                                       C.sub.6 H.sub.5 CH.sub.2                                                                H  H   2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                   H  Br 170-172                                       __________________________________________________________________________

EXAMPLE 6

The procedure of Example 4 is again repeated, starting with therequisite reagents, to provide the following imidazo[2,1-b]thiazoliumsalts:

2-methyl-3,4-diethyl-7-benzylimidazo[2,1-b]thiazolium chloride;2-n-propyl-3,4-diethyl-7-(p-fluorobenzyl)imidazo[2,1-b]thiazoliumchloride, 2-i-propyl-7-(p-fluorobenzyl)imidazo[2,1-b]thiazoliumchloride; 3-phenyl-7-(o-methoxybenzyl)imidazo[2,1-b]thiazolium bromide;3-adamantyl-6-phenyl-7-(m-trifluorobenzyl)imidazo[2,1-b]thiazoliumbromide; 3-(3,5-dimethoxybenzyl)-7-benzylimidazo[2,1-b]thiazoliumchloride, 3-methyl-7-(p-phenylbenzyl)imidazo[ 2,1-b]thiazolium bromide;3-(2,4-dimethylbenzyl)-6-methyl-7-(p-chlorobenzyl)-imidazo[2,1-b]thiazoliumbromide; 3-(p-chlorophenyl)-7-propargylimidazo[2,1-b]-thiazoliumbromide; 3,6-bis(2,4-dimethylphenyl)-7-benzylimidazo[2,1-b]thiazoliumchloride;1-(p-fluorobenzyl-5,6,7,8-tetrahydroimidazo[2,1-b]benzthiazoliumchloride and 1-propargyl-5,6,7,8-tetrahydroimidazo[2,1-b]benzthiazoliumbromide.

EXAMPLE 7 3-Methyl-9-benzylthiazolo[3,2-a]benzimidazolium bromide (R₁ =C₆ H₅ CH₂ : R₂ = H; R₃ = CH₃ ; R₄ and R₅ = --CH=CH--CH=CH--; X = Br)

Starting with 3-methylthiazolo[3,2-a]benzimidazole and benzyl bromideand repeating the procedure of Example 1, the desired product isobtained, m.p. 227°-229° C.

EXAMPLE 8

The procedure of Example 1 is repeated wherein the appropriate thiazolo[3,2-a]benzimidazole is condensed with the requisite halide to providethe following quaternary salts:

    ______________________________________                                         ##STR7##                                                                     R.sub.1        R.sub.2  R.sub.3      X                                        ______________________________________                                        C.sub.6 H.sub.5 CH.sub.2                                                                    CH.sub.3                                                                              H              Cl                                       m-ClC.sub.6 H.sub.4 CH.sub.2                                                                CH.sub.3                                                                              CH.sub.3       Br                                       p-ClC.sub.6 H.sub.4 CH.sub.2                                                                CH.sub.3                                                                              CH.sub.3       Cl                                       p-FC.sub.6 H.sub.4 CH.sub.2                                                                 H       C.sub.6 H.sub.5                                                                              Cl                                       m-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                        H       C.sub.6 H.sub.5                                                                              Cl                                       m-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                        CH.sub.3                                                                              C.sub.6 H.sub.5                                                                              Cl                                       m-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                         H       2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         Cl                                        ##STR8##     H       2,4-(CH.sub.3).sub.2 C.sub.6 H.sub.3                                                         Br                                        ##STR9##     H       C.sub.6 H.sub.5                                                                              Br                                       p-C.sub.6 H.sub.5 C.sub.6 H.sub.4 CH.sub.2                                                  H                                                                                      ##STR10##     Br                                       2,4-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                       H       2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                       Cl                                       2,6-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                       H       2,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3                                                       Cl                                       3,5-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                       H       C.sub.2 H.sub.5                                                                              Cl                                       m-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                        C.sub.2 H.sub.5                                                                       C.sub.2 H.sub.5                                                                              Br                                       ______________________________________                                    

EXAMPLE 9

The procedure of Example 1 is again repeated, wherein the requisitethiazolo[3,2-a]benzimidazole is condensed with the appropriate halide toprovide the following quaternary salts:

    ______________________________________                                         ##STR11##                                                                    R.sub.1          R.sub.2                                                                              R.sub.3 X    m.p., ° C.                        ______________________________________                                        C.sub.6 H.sub.5 CH.sub.2                                                                       H      CH.sub.3                                                                              Br   229-231                                  n-C.sub.16 H.sub.33                                                                            H      CH.sub.3                                                                              Br   160-1                                    C.sub.2 H.sub.5  H      CH.sub.3                                                                              Br   284                                       ##STR12##       H      CH.sub.3                                                                              Cl   227-9                                     ##STR13##       H      CH.sub.3                                                                              Br   197-8                                     ##STR14##       H      CH.sub.3                                                                              Cl   234                                      CH.sub.2CH . CH.sub.2                                                                          H      CH.sub.3                                                                              Br   256-7                                     ##STR15##       H      CH.sub.3                                                                              Cl   233-5                                     ##STR16##       H      CH.sub.3                                                                              Cl   233-6                                     ##STR17##       H      CH.sub.3                                                                              Br   314-5                                     ##STR18##       H      CH.sub.3                                                                              Br   243-4                                     ##STR19##       H      CH.sub.3                                                                              Cl   218-9                                     ##STR20##       H      CH.sub.3                                                                              Br   252                                      ______________________________________                                    

EXAMPLE 10 3-Methyl-7-benzylimidazo[2,1-b]thiazolium Chloride

A. A solution of 3.09 g. of 3-methyl-7-benzylimidazo[2,1-b]thiazoliumbromide in 35 ml. of water is treated with 1.15 g. of silver oxide andthe mixture allowed to stir at room temperature for several hours. Thereaction mixture is centrifuged and the supernatant decanted from thesilver bromide. Aqueous hydrochloric acid (11 ml. of a 1 M solution) isadded to the clear supernatant and the water removed in vacuo. Theresidual quaternary salt is triturated with diethyl ether andsubsequently filtered and recrystallized from acetonitrile-ethylacetate.

In a similar manner the quaternary bromide salts in Examples 1 through 8are converted to the quaternary chloride salts.

B. The procedure of Example 10A is repeated, 1.8 ml. of 6 N nitric acidbeing substituted for the 11 ml. of 1N hydrochloric acid, to provide3-methyl-7-benzylimidazo[2,1-b]thiazolium nitrate.

EXAMPLE 11

In a manner similar to that in Example 10, the quaternary chloride andbromide salts prepared in Examples 1 through 9 are converted to otherquaternary salts wherein the anion of the resulting salt, X, is apharmaceutically acceptable anion.

EXAMPLE 12 Hypoglycemic Testing

The hypoglycemic testing of the compounds of the present invention iscarried out by a standard procedure, and comprises grouping eight,Hartley strain, male guinea pigs which have been fasted 18-24 hrs. ineach group. Blood samples are obtained from thepentobarbital-anesthetized animals by cardiac puncture. Each of theeight animals is dosed i.p. with a given dose of the test compound.Blood samples are taken at 1, 2 and 4 hours following the dosing, andthe venous blood diluted 1:10 with saline and assayed for blood sugarlevels on an Auto-Analyzer, the levels being expressed as mg.%. Theactivity for the test compound is expressed as the percent lowering ofthe blood sugar at the 1, 2 and 4 hr. when compared with the blood sugarlevel of a group of eight control animals which have been similarlydosed with a saline solution.

Each of the following representative imidazo[2,1-b]thiazolium salts wastested as hypoglycemic agent following the above mentioned procedure,and was found to be active at the indicated dose level. ##STR21##

    __________________________________________________________________________                                      % Fall Blood-                                                                 Sugar Level                                 R.sub.1  R.sub.2                                                                          R.sub.3                                                                              R.sub.4                                                                          R.sub.5                                                                          X Dose, mg./kg.                                                                        T.sub.1                                                                          T.sub.2                                                                          T.sub.4                               __________________________________________________________________________    C.sub.6 H.sub.5 CH.sub.2                                                               H  CH.sub.3                                                                             H  H  Br                                                                              50     36 82 88                                    C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                      H  CH.sub.3                                                                             H  H  Br                                                                              50     12 17 --                                    m-ClC.sub.6 H.sub.4 CH.sub.2                                                           H  CH.sub.3                                                                             H  H  Br                                                                              50     18 45 79                                    p-C.sub.6 H.sub.5 C.sub.6 H.sub.5 CH.sub.2                                             H  CH.sub.3                                                                             H  H  Br                                                                              100    43 60 --                                    C.sub.6 H.sub.5 CH.sub.2                                                               H  C.sub.6 H.sub.5                                                                      H  H  Br                                                                              100    30 29 22                                             H  CH.sub.3                                                                             H  H  Br                                                                              50     -- 18 20                                    C.sub.6 H.sub.5 CH.sub.2                                                               (CH.sub.2).sub.4                                                                        H  H  Br                                                                              50     45 87 --                                    p-ClC.sub.6 H.sub.4 CH.sub.2                                                           H  CH.sub.3                                                                             H  H  Cl                                                                              50     8  18 42                                    2,4-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                  H  CH.sub.3                                                                             H  H  Cl                                                                              50     20 48 --                                    p-FC.sub.6 H.sub.5 CH.sub.2                                                            H  CH.sub.3                                                                             H  H  Cl                                                                              50     16 38 77                                    C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3                                                                         CH.sub.3                                                                             H  H  Br                                                                              50     14 45 62                                    C.sub.6 H.sub.5 CH.sub.2                                                               H  H      H  H  Br                                                                              50     40 76 86                                    m-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                    H  CH.sub.3                                                                             H  H  Cl                                                                              50     -- 10 12                                    C.sub.6 H.sub.5 CH.sub.2                                                               H                                                                                 ##STR22##                                                                           H  H  Br                                                                              50     11 15 32                                    __________________________________________________________________________

    __________________________________________________________________________    and                                                                            ##STR23##                                                                                                    % Fall Blood-                                                             Dose,                                                                             Sugar Level                                   R.sub.1    R.sub.2                                                                          R.sub.3                                                                           R.sub.4                                                                             R.sub.5                                                                         X mg./kg.                                                                           T.sub.1                                                                           T.sub.2                                                                           T.sub.4                               __________________________________________________________________________    C.sub.6 H.sub.5 CH.sub.2                                                                H  H   CH.sub.3                                                                            H  Br                                                                              50  29  68  79                                    C.sub.6 H.sub.5 CH.sub.2                                                                H  CH.sub.3                                                                          H     H  Br                                                                              25  20  62  66                                    p-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                    H  CH.sub.3                                                                          H     H  Cl                                                                              100 33  83  --                                    p-ClC.sub.6 H.sub.4 CH.sub.2                                                            H  CH.sub.3                                                                          H     H  Cl                                                                              25  11  16  39                                    2,4-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                   H  CH.sub.3                                                                          H     H  Cl                                                                              50  8   65  --                                    C.sub.6 H.sub.5 CH.sub.2                                                                H  H   C.sub.6 H.sub.5                                                                     H  Br                                                                              25  6   26  84                                    C.sub.6 H.sub.5 CH.sub.2                                                                H  H   p-ClC.sub.6 H.sub.4                                                                 H  Br                                                                              50  5   35  78                                    C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                       H  CH.sub.3                                                                          H     H  Br                                                                              50  26  70  85                                    and                                                                                         ##STR24##     50  18  32  66                                    __________________________________________________________________________

EXAMPLE 13 3-Methyl-7-benzylimidazo[2,1-b]thiazolium chloride

A column 1 inch × 20 inches is packed with Amberlite IRA-400 which hasbeen slurried in 2N sodium hydroxide solution. After the column materialis washed with deionized water, a solution of 5.0 g. of3-methyl-7-benzylimidazo[2,1-b]-thiazolium bromide in 50 ml. of water isapplied. The water eluates are collected until the pH of said eluates isneutral. The combined eluates are treated with 200 ml. of 6Nhydrochloric acid and concentrated to dryness. The crystallized productis further purified by recrystallization from acetonitrileethyl acetate,1.22 g., m.p. 152°-155° C.

In a similar manner the quaternary salts of Examples 1 through 8 areconverted to other quaternary salts wherein the resulting salt anion, X,is a pharmaceutically acceptable one.

EXAMPLE 14 3-methyl-7-Styryl-5,6-dihydro-imidazo[2,1-b]thiazoliumchloride

a. The compound 3-methyl-7-phenacyl-5,6-dihydro-imidazo[2,1-b]thiazoliumchloride is prepared by the method of Example 1, using phenacyl chlorideinstead of propargyl bromide. This compound has a m.p. 162°-4° C. and isused in the next stage.

b. The product of (a) (23.4 g.) is dissolved in water (60 ml.) andstirred at room temperature while sodium borohydride (0.8 g.) is addedin portions. After 5-10 min. the solution is acidified with conc.hydrochloric acid and evaporated to dryness, using dioxan to remove thelast of the water by azeotropy. The residue is extracted with boilingacetonitrile (150 ml.), filtered, and hot ethyl acetate (100 ml.) isadded to the hot filtrate. On cooling, the N-(2-hydroxy-2-phenylethylcompound crystallizes 12.7 g., as colourless plates and isrecrystallized from acetonitrile-ethyl acetate, m.p. 195° .

c. The product of (b) (12.5 g.) dissolved in benzoyl chloride (40 ml.)is stirred and heated on a silicone oil bath at 200° for 1 hr., thencooled. After standing at 0° overnight the solid is filtered off, washedwith acetone and then ether, and recrystallized from acetonitrile (witha little methanol added) to give the desired styryl product (5.5 g.), aspale yellow platelets, m.p. 280° (decomp.),

Anal. Calc'd for C₁₄ H₁₅ ClN₂ S: Cl, 1, 12.7; N, 10.0 Found: C, 12.4; N,9.9

What is claimed is:
 1. A compound of the formula ##STR25## wherein X isa pharmaceutically acceptable anion; R₁ is selected from the groupconsisting of alkyl having from twelve to eighteen carbon atoms andallyl;R₂ is selected from the group consisting of hydrogen and alkylhaving from one to three carbon atoms; R₃ is selected from the groupconsisting of hydrogen, alkyl having from one to three carbon atoms,adamantyl, phenyl and substituted phenyl wherein said substituent isselected from the group consisting of dimethyl and dimethoxy; R₂ and R₃when taken together are tetramethylene; R₄ is selected from the groupconsisting of hydrogen, alkyl having from one to three carbon atoms,phenyl, dimethylphenyl, and chlorophenyl and R₅ is hydrogen.
 2. Acompound of claim 1 wherein X is bromo, R₁ is alkyl having from twelveto eighteen carbon atoms, R₂, R₄ and R₅ are each hydrogen and R₃ isalkyl having from one to three carbon atoms.
 3. The compound of claim 2,7-cetyl-3-methyl-5,6-dihydroimidazo[2,1-b]thiazolium bromide.